The immune system serves to protect the host from invasion by foreign organisms by distinguishing “self” from “nonself.” When the immune system recognizes host antigens (autoantigens) as foreign, autoimmune disease results, causing tissue destruction and functional impairment (See, e.g. Tlaskalova-Hogenova, et al., Folia Microbiol., 43:545-550 [1998]). One example of an autoimmune disease is Inflammatory Bowel Disease (“IBD”).
IBD is defined by chronic, relapsing intestinal inflammation of obscure origin. IBD includes two distinct disorders, namely, Crohn's disease and ulcerative colitis (UC). Both diseases appear to result from the unrestrained activation of an inflammatory response in the intestine. This inflammatory cascade is thought to be perpetuated through the actions of proinflammatory cytokines and activation of selective lymphocyte subsets. In patients with IBD, ulcers and inflammation of the inner lining of the intestines lead to such symptoms as abdominal pain, diarrhea, and rectal bleeding. Ulcerative colitis occurs in the large intestine, while in Crohn's disease, the disease can involve the entire gastrointestinal (GI) tract as well as the small and large intestines. For most patients, IBD is a chronic condition with symptoms lasting for months to years. It is most common in young adults, but can occur at any age. It is found worldwide, but is most common in industrialized countries such as the United States, England, and northern Europe. The clinical symptoms of IBD are intermittent rectal bleeding, crampy abdominal pain, weight loss and diarrhea Diagnosis of IBD is often based on the clinical symptoms and/or the use of a barium enema, but direct visualization (sigmoidoscopy or colonoscopy) is the most accurate test. Protracted IBD is a risk factor for colon cancer, and treatment of IBD can involve medications and surgery.
Some patients with UC only have disease in the rectum (proctitis). Others with UC have disease limited to the rectum and the adjacent left colon (proctosigmoiditis). Yet others have UC of the entire colon (universal IBD). Symptoms of UC are generally more severe with more extensive disease (e.g. where a larger portion of the colon is involved with disease).
The prognosis for patients with disease limited to the rectum (proctitis) or UC limited to the end of the left colon (proctosigmoiditis) is better than that of patients whose disease affects the entire colon. Brief periodic treatments using oral medications or enemas may be sufficient. In those with more extensive disease, blood loss from the inflamed intestines can lead to anemia, and may require treatment with iron supplements or even blood transfusions. Rarely, when the inflammation becomes very severe, the colon can acutely dilate to a large size. This condition is called “toxic megacolon.” Patients with toxic megacolon are extremely ill with fever, abdominal pain and distention, dehydration, and malnutrition. Unless the patient improves rapidly with medication, surgery is usually necessary to prevent colon rupture.
Crohn's disease can occur in all regions of the gastrointestinal tract. Intestinal obstruction due to inflammation and fibrosis occurs in a large number of patients. Abscesses and fistula formation are frequent complications of Crohn's disease. Disease progression consequences include intravenous feeding, surgery and colostomy.
Colon cancer is a known complication of chronic IBD. It is increasingly common in those patients who have had extensive IBD over many years. The risk for cancer begins to rise significantly after eight to ten years of IBD.
Several treatments exist for IBD, including medication, nutritional therapy, and surgery (See e.g., Evans and Ciclitira, The Practitioner, 243:307-314 [1999]; Rampton, Brit. Med. J., 319:1480-5 [1999]; and Stein and Hanauer, Gastroenterol. Clin., 28: 297-321 [1999]). Patients who wish to avoid corticosteroids (especially children) are often treated with a liquid formula diet. The diet is given as the only nutritional source for 4-6 weeks. However, the usefulness of dietary treatment is limited by the expense of formulations and the high rate of relapse following discontinuation.
The most commonly used medications to treat IBD are anti-inflammatory drugs such as the salicylates. Examples of salicylates include sulfasalazine, and the newer drug mesalazine. Mesalazine is given orally in high doses for maximal therapeutic benefit. The salicylate preparations have been effective in treating mild to moderate disease. However, these drugs, including newer medications such as mesalazine are not without side effects such as headache, nausea, diarrhea, pancreatitis, as well as blood dyscrasias and interstitial nephritis in some patients. Nonetheless, these drugs can also decrease the frequency of disease flares when the medications are taken on a prolonged basis. However, a four month course of high dose mesalazine induced remission in only 40% of patients with mildly active Crohn's disease (Rampton, Brit. Med. J., 319:1480-5 [1999]).
Corticosteroids are more potent and faster-acting than salicylates in the treatment of IBD, but potentially serious side effects limit the use of corticosteroids to these patients with more severe disease. Side effects of corticosteroids usually occur with long term use. They include thinning of the bone and skin, infections, diabetes, muscle wasting, rounding of faces, psychiatric disturbances, and, on rare occasions, destruction of hip joints.
In IBD patients that do not respond to salicylates or corticosteroids, medications that suppress the immune system are used. Examples of immunosuppressants include azathioprine and 6-mercaptopurine. Immunosuppressants used in this situation help to control IBD and allow gradual reduction or elimination of corticosteroids. However, immunosuppressants render the patient immuno-compromised and susceptible to many other diseases.
Patients who fail to respond to dietary or drug therapy require surgical resection. However, surgery is often not curative and 50% of patients require additional surgery. There remains a great need for agents capable of preventing and treating IBD. In particular, agents suitable for administration in a cost-effective and timely fashion, with a minimum of adverse side effects are needed. The present invention, as described below, provides treatments for IBD that solve many of the problems of the currently available treatments.